ABSTRACT Butadiene is an important tobacco smoke carcinogen likely to be involved in the induction of lung tumors in smokers. Butadiene is classified as a known human carcinogen based on epidemiological evidence indicating increased cancer incidence in occupationally exposed workers and in inhalation studies in laboratory animals. The recognized critical step in butadiene-mediated carcinogenesis is the chemical modification of DNA by the epoxide metabolites of butadiene to form covalent adducts. Previous studies have shown that genetic variations in metabolism and repair genes can mediate the sensitivity to butadiene-induced mutations and cancer. Because of the requirement for metabolic activation of butadiene, enzymes that are involved in the formation and detoxification of butadiene epoxides largely determine the individual sensitivity to butadiene-mediated mutagenesis and carcinogenesis. Many prominent polymorphisms in genes coding for butadiene metabolizing enzymes have been identified. Because their frequency differs between ethnic/racial groups, these genetic changes may contribute to the observed inter-ethnic/inter-racial differences in the incidence of lung cancer. In the previous funding period, we observed significant ethnic differences in the excretion of urinary butadiene-mercapturic acids by White, African American, Japanese American, and Native Hawaiian smokers. These results indicate that these ethnic groups metabolize butadiene differently due to genetic variations in biotransformation genes such as glutathione-S-transferase 1 (GSTT1). We now hypothesize that due to ethnic variations in butadiene metabolism, human populations of different ethnicity/race form different numbers of butadiene-DNA adducts, which contributes to ethnic disparities in cancer risk following exposure to butadiene in tobacco smoke. The objective of this application is to investigate inter-individual and inter-ethnic/racial differences in formation of butadiene- induced DNA adducts in smokers, to establish their role in lung cancer risk, and to link inter-individual differences in response to butadiene to specific polymorphisms of carcinogen metabolism and DNA repair genes. Our approach is innovative because we will, for the first time, examine butadiene-DNA adduct formation in a large multi-ethnic cohort of smokers, evaluate the association between butadiene exposure and lung cancer, and evaluate the effects of specific genetic polymorphisms on butadiene metabolism, DNA adduct formation, toxicity, and mutations in human HapMap cell cultures. Expected outcomes: Although smoking is a recognized risk factor for lung cancer, one out of five Americans continue to smoke. About 11-24 % of smokers will develop lung tumors over the lifetime, with a greater cancer incidence in African American and Native Hawaiian cigarette smokers as compared with European Americans, Japanese Americans, and Latinos. Our studies will help provide insight into the origins of this variability in sensitivity to smoking-mediated lung cancer and help identify individuals at risk who should be candidates for special smoking cessation intervention or chemopreventive therapy.